6-substituted ring a aromatic steroids



United States Patent ,257,391 G-SUBSTITUTED RING A AROMATIC STEROIDSAlbert Bowers and Otto Halpern, Mexico City, Mexico, assignors to SyntexCorporation, Panama, Panama, a corporation of Panama J No Drawing. FiiedDec. 11, 1963, Ser. No. 329,85 Claims priority, application Mexico, Mar.27, 1963,

20 Claims. (61160-23955) The present invention relates to a novelprocess for making cyclopentanoperhydrophenanthrene derivatives andtocertain novel compounds obtained by this method.

More particularly the present invention relates to a process for making3-hydroxy ring A aromatic steroids of the androstane, pregnane andsapogenin series, which may be further substituted at C-6 by a loweralkyl, alkenyl or alkinyl groups, from the corresponding A -3-hydroxysteroids, as well as to the novel 6-substituted derivatives.

The novel compounds obtained by our methods are represented by thefollowing formulas:

1:0 (\ijimuRa R4 such as methyl, ethyl, propyl, vinyl, ethinyl orpropargyl;

R represents hydrogen, hy-droxy or acyloxy; R represents hydrogen,u-methyl, ,B-methyl, oc-l'lYdIOXY or a-acyloxy; R together with thehydroxyl group at C17oc may also represent the radical 3,257,391Patented June 21, 1966 wherein A represents hydrogen or a lower alkylradical and B represents a lower alkyl, an aryl or aralkyl radicalcontaining up to 10 carbon atoms, and Z represents hydrogen, fl-hydroxyor a keto group.

The acyl and acyloxy groups above referred to are derived fromhydrocarbon carboxylic acids containing less than 12 carbon atoms whichmay be saturated or unsaturated, of straight, branched, cyclic orcyclic-aliphatic chain, or aromatic, and may be substituted byfunctional groups such as hydroxy, alkoxy containing up to 5 carbonatoms, acyloxy containing up to 12 carbon atoms, nitro, amino orhalogen. Typical ester groups are the acetate, 'propionate, enant'hate,zenzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, amino acetate, and p-chloropropionate.

The novel compounds of the invention are estrogenic type hormones whichshow anti-androgenic action and a relatively small feminizing affect.They are useful in fertility control. In addition, these compounds arevaluable intermediates for the production of 19-nor steroids, which areknown active progestational agents.

Several methods have been described in the literature for the productionof ring A aromatic steroids starting from the A -3-keto or A -3-ketocompounds, by thermal degradation [H. H. Inh-offen, Angew. Chem. 53, 471(1940)], by pyrolysis in a mineral oil [0. Djerassi et al., J. Am. Chem.Soc. 72, 4534 (1950') and ibid. 73, 1523 (1951) and E. B. Hershberg etal., J. Org. Chem. 15, 292 (1950)]. However, due to the drasticconditions, the use of these methods is very limited because they cannotbe applied to steroid compounds having substituents unstable to heatespecially at temperatures around 600 C. Moreover, very low yields areobtained.

The aromatization of ring A in steroid compounds by means of acid hasalso been described by C. Djerassi et al., J. Am. Chem. Soc. 72, 4540(1950); however, migration of the angular methyl group to ring A occursin this case.

In accordance with the present invention the surprising discovery hasbeen made that when a 3-hydroxy-A 19-nor-steroid of the androstane,pregnane and sapogenin series is treated with an oxidizing agent,capable of oxidizing secondary alcohols to ketones, there are obtainedthe corresponding A -estratriene compounds, in very good yields, asillustrated by the following equation, wherein only rings A and B of thesteroid molecule are In the above formulas, X represents hydrogen or analiphatic hydrocarbon radical of up to 6 carbon atoms.

The starting materials used in the process of the present invention arethe 3-hydroxy-A -19-nor-stero-ids of the androstane, pregnane orsapogenin series, or the 6-substituted derivatives thereof which areobtained by lithium aluminum hydride reduction or treatment with aGrignard reagent of the 3-acyloXy-A -19-nor-6 keto steroids, followed byacid treatment of the 3,6-dihydroxy or 6-substituted 3,6-dihydroxycompounds, as described in our copending applications Serial Nos.293,831 and 293,898, filed July 9, 1963. i

6 The starting materials may have at C-17 a keto group,

an acyloxy group, a l7,B-l1ydroxyl group which may further possess a17a-lower alkyl, alkenyl or alklnyl radical,

a 17fi-acetyl radical with or without a hydroxyl or acyloxy group at C-17a, or the dihydroxyacetone side chain protected as the17,20;20,2l-bismethylenedioxy derivative. There may further be othergroups in the molecule of the starting compound which do not interferewith the reaction, such as for example, when there is a 17,8-acetylsubstituent, a double bond between C-16 and C17, or -a 16u,17a-diol,preferably protected as the acetonide; an

ll-ketone or 11,6-hydroxyl group particularly in the case of compounds.having'a 17-dihydroxyacetone side chain; a methyl group at 160: or16,8, etc.

As suitable starting materials, there can be used the followingcompounds:

A -19-nor-androstadien-3 ,B-ol-17-one,

'17-acetate of 4 -19-nor-pregnadien-3/3,17a-diol-2O- one,

17-acetate of 16a-met-hyl-A -pregnadiene-3B,17a-

diol--one,

A -19-nor-pregnadiene-35,17ot-diol-20-one,

' 17,20;20,21-bismethylenedioxy-A -19-norpregnadien-Sfi-ol, 17,20;20,21-bismethylenedioxy-A -19-norpregnad-ien-Iifl-ol-l l-one, 1 17,20;20,21abismethy'lenedioxy-A -19-norpregnadiene-3/3,11fl-diol,

6-methyl-17,20 ;20,21-bismethylenedioxy-A l9-norpregnadien-3 B-ol,

' 6-ethinyl-17,20;20,2l-bismethylenedioxy-N -19-norpregnadien-3fi-ol andA l -19-nor-22-isospirastadien-3fl-ol.

As indicated hereinbefore, a-ny oxidant capable of oxidizing secondaryalcohols to ketones may be used in practicing the process of the presentinvention; the reaction conditions (amount of reagents, solvents,temperature, reaction period of time, etc.), depend on the oxidant used,but are in general no different than those conventionally used for theoxidation of secondary alcohols to ketones.

Among the reagents suitable for use in this process are Op'penauerreagents such as aluminum isopropoxide, aluminum t-butoxide and aluminumphenoxide; chromium trioxide in aqueous acetic acid, chromiumtrioxide-pyridine complex, a solution of chromium trioxide in acetonepreferably about 8 N and in the presence of sulfuric acid, sodium orpotassium dichromate. in aqueous acetic acid, N-haloamides, N-haloimidesand the like.

Where Oppenauer conditions are used the 3-hydroxy- A -19-nor-steroid istreated with an excess of an aluminum alkoxide, in an organic solventand in the presence of a hydrogen acceptor. The reaction is generallyconducted at reflux temperature for a period of time in the order of 1to 12 hours, however, it may be carried out at lower temperatures, for aprolonged period of time.

Among the aluminum alkoxides which can be used in this process are:aluminum isop-ropoxide, aluminum tbutoxide, aluminum phenoxide or anyother alkoxide commercially available; chloromagnesium alkoxides orpotassium-t-butoxide may also be employed as catalysts.

As hydrogen acceptors the preferred reagent used is cyclohexanone;however, other ketones may be used, such as acetone, methyl ethylketone, diethylketone, benzoquisulfate and evaporated to dryness.

none, etc. Organic solvents are preferably non polar solvents such astoluene, xylene, benzene, and the like.

In general, the conditions for the Oppenauer oxidation used in the novelmethod are those described by C. Djerassi in Organic Reactions, vol. VI,p. 207 (John Wiley and Sons, Inc.).

The transformations of A -19-nor steroids into the corresponding ring Aaromatic compounds using chmmium trioxide as the oxidizing agent iseffected under the usual reaction conditions. Thus, for example, theremay be used from 1 to 2 molar equivalents of chromium trioxide, inaqueous acetic acid solution, at a temperature between 15 to 18 C., andfor a period of time of 1 to 3 hours. An 8 N solution of chromic acid inacetone and in the presence of sulfuric acid (Jones reagent) may also beemployed.

The chromium trioxide-pyridine'complex oxidation is conducted preferablyat room temperature, for a period of time of between 6 to 24 hours.Potassium or sodium dichromate are used in acetic acid-benzene solution,at room temperature and for 15 to 24 hours.

When the reagents used in the novel method are the N-haloamides orN-haloimides, such as .for example, N- bromoacetamide, orN-bromosuccinimide the reaction is preferably conducted in aqueous-t-butanol solution and in the presence of pyridine, at low temperature,and for a period of time of 12 to 24 hours.

Example I A solution of 5 g. of A -19-nor-androstadien-3fi- 0l-l7-or1ein cc. of dry toluene and 15 cc. of cyclohexanone was dried bydistilling ofi? 10 cc. of the solvent. A solution of 5 g. of aluminumisopropoxide dissolved in 35 cc. of anhydrous toluene was then added andthe mixture was refluxed for 45 minutes; 10 cc. of acetic acid wereadded .and the solvents removed by steam distillation. The product wasextracted several times with ethyl acetate and the organic extractswashed with 5% hydrochloric acid solution, water, 10% sodium carbonatesolution and 'water until neutral, dried over anhydrous sodium sulfateand evaporated to dryness. The residue was crystallized fromacetone-hexane to produce 4.1 g. Ovf est-rone, identical to an authenticsample.

Example II Example III In the method of Example I aluminum phenoxide wasused instead of aluminum isopropoxiide with the same results.

Example I V From a mixture of 1 g. of A -19-nor-androstadien-3,8-ol-l7-0ne, 60 cc. of anhydrous toluene and 6 g. of benzoquinonethere were distilled 10 cc. to eliminate moisture. 1 g. of aluminumt-butoxide dissolved in 10 cc. of anhydrous toluene was then added andthe mixture refluxed for 1 hour under anhydrous conditions. 5 cc. ofacetic acid were then added and the toluene was eliminated by steamdistillation, extracted with ethyl acetate and the organic extractwashed with potassium hydroxide solution and water to neutral dried overanhydrous sodium Crystallization of the residue from acetone-hexaneafforded also estrone in 75% yield.

Example V In the method of Example I, acetone cc.) was nique for theisolation of the product there was obtained estrone in 78% yield.

Example VI Example VII The preceding example was repeated but usingmethylethyl-ketone instead of acetone to produce also17a-methyl-estradiol in similar yield.

Example VIII From a solution of 1 g. of 17a ethiny1-A iandnos tadiene35,176 diol in 50 cc. of anhydrous xylene and 10 cc. of cyclohexanonethere were distilled 10 cc. to eliminate moisture. A solution of 1 g. ofaluminum t-butoxide dissolved in 5 cc. of xylene was added dropwise andthe solution was refluxed with slow distillation for an hour further. 5cc. of acetic acid were added and the solvents eliminated by steamdistillation. The product was collected by filtration, washed with waterand crystallized from acetone-hexane, thus producing17aethinyl-esteradiol identical to an authentic sample.

Example IX In accordance with the method described in Example I, thecompounds below mentioned (I), were converted into the corresponding.aromatic compound (II):

G-ethinyl-A -l9-nor-pregnadien- 3B-ol-20-one.

6,16a-dimethyl-A -19-norpregnadien-SB-ol-20-one.

17-acetate of A100) -19-nor-pregna- (Ilene-33,17a-di0l-20-one.

one.

A -19-nor-22-isospirostadien-- 6a-propargyl-l7a-rnethyl-estradiol.

6a,17a-diethinyl-estradiol.

A -l9-nor-pregnatrien-3'o120- one. lfia-rnethyl-A-19-nor-pregnatrien-3ol-20-0ne. 16a,17a-isopropylidenedioxy- A-1Q-nor-pregnatrien-B-ol- 20-one. 17,20;20,21-bismethylenedioxy- A-19-nor-pregnatrien-3-ol. BLx-methyl-A -19-nor-pregnatrien-3-ol-20-one.6a-methyl-17,20;20,21-bis1nethylenedioxy-A -19-n0r-pregnatrien-3-ol.fia-vinyl-A B 19-11or-pregnatrien-3-ol-20-one. tim-ethinyl-A-19-nor-pregnatrien-3-ol-20 one. 6a,16a-dimeth v1-A-19-norpregnatrien-3-ol-20-one.

fia-methyl-lda,17a-isopropylidenepregnatriene-B,171x-diol-20-one.17-acetate of IGa-methyl-A V500)- 19'nor-pregnatriene-3,17a-diol-20-one. 17-acetate of fia-vinyl-lfia-methyl- A JQnOr-pregnatfiene-3,17a-diol-20-one. A ;.5;1 -19-nor-22-isospirostatrien- 6 Example X Inaccordance with the method described in Example II, 1 g. of the.17-acetate of 16a-methyl-A -19-norpregnadiene-3/L'l7a-diol-20-one wastreated with aluminum t-butoxide in toluene solution and in the presenceof cyclohexanone, to give the 17-acetate of Ma-methyl- A -19-norpregnatriene-3,l7a-diol-20 one, identi- I cal to the obtained in thepreceding example.

A mixture of 500 mg. of the foregoing triene, 2O cc.of methanol and 100mg. of potassium hydroxide previously dissolved in 1 cc. of water wasrefluxed for 1 hour, poured into water and the formed precipitatecollected by filtration. There was thus obtained l6a-methy1-Al9-nor-pregnatriene-3,l7a-diol-20-one.

Example XI A solution of 2 g. of A -19-nor-p-regnadien-3p-o1- 20-one in40 cc. of pyridine was added to a mixture of 2 g. of chromium trioxidein 40 cc. of pyridine. The reaction mixture was kept at room temperatureovernight. It was then diluted with ethyl acetate, filteredthroughcelite and the filtrate washed Well with water, dried and evaporated todryness. The residue was crystallized from acetone-hexane, to produce A-l9-nor-pregnat-rien-3-o1-20-one, identical to that obtained in ExampleIX.

Example XII A solution of 500 mg. of chr-omic acid in 5 cc. of aceticacid was added dropwi-se to a stirred solution of 1 g. of the l7-acetate of A -l9-nor-pregnadiene-3B,- 17a-diol20-one in 20 cc. ofglacial acetic acid, while the temperature was maintained around 20 C.After 2 hours at room temperature, the mixture was poured into ice waterand the formed precipitate collected, washed with water andrecrystallized from methanol, thus giving the 17-acetate of M-l9-nor-pregnatriene-3,l7adio'l-20-one identical .to that obtained bythe method of Example I.

In the same manner starting from A-19-norpregnadiene-Sfl,17a-diol-20-one there was obtained M-19-nor-pregnatriene-3, 17a-diol-2O-one.

Example XIII A solution of 1 g. of A -19-n-or-androstadien-3B- ol-17-onein' 10 cc. of acetone was cooled to 0 C. and treated under an atmosphereof nitrogen and with stirring, with a solution of 8 N chI-omic acid(prepared by mixing 26 g. of chromium trioxide with 23 cc. ofconcentrated sulfuric acid and diluting with water to cc.) until thecolor of the reagent persisted in the mixture. It was stirred for 4hours funther at 05 C. and diluted with water. The precipitate wascollected, washed with water and dried under vacuum, to produce alsoestrone which was purified by crystallization from acetone-hexane.

Example XIV By following the method described in the preceding example,l g. of 17,20;20,2l-bismethylenedioxy-A l9-nor-pregnad-ien-3B-ol wasconverted into 17,20;20-21- bismethylenedioxy-N-19-nor-pregnatrien-3-ol.

The foregoing compound was dissolved in 20 cc. of 60% formic acid andthe resulting solution was heated on the steam bath for 1 hour, cooled,diluted with water and extracted with ethyl acetate; the extract waswashed to neutral, dried and evaporated to dryness. Crystallization ofthe residue from acetone-ether gave A -19-nor-pregnatriene-3,l7a,21-triol-20 one.

Example XV The preceding example was repeated but using 17,20;- 20,21bismethylenedioxy-A -19-nor pregnadiene- 3,6,1lfl-diol as startingmaterial, thus producing successively 17,20;20,21 bismethylenedioxy A-19-nor Example VI.

Example XVI Example XVII To a cold solution of 1 g. of A-19-nor-andr0stadiene-3B-ol-17-one in cc. of t-butyl-alcohol, 1 cc. of

water and 1 cc. of pyridine there were added 2 molar equivalents ofN-bromoacetamide and the reaction mixture was kept at 0 C. overnight. Itwas then diluted with water, extracted with methylene chloride and theorganic extract washed with dilute hydrochloric acid and water toneutral, dried over anhydrous sodium sulfate and evaporated to dryness.The residue was crystallized from acetone-hexane to produce also estronein similar yields to those of the preceding examples.

Example XVIII The preceding example was repeated but using N-bromosuccinimide instead of N-bromoacetamide with the same results.

Example XIX To a solution of 2.5 g. of 6aethinyl-estrone in 10 cc. ofacetone there was added a solution of 7 g. of potassium hydroxide in 5cc. of water, and the stirred mixture 8 methyl-A-19-nor-pregnatrien-3-ol 20 one, 16amethyl-A-19-nor-p-regnatrien-B-ol-ZO-one, Got-vinyl- A-19-nor-pregnatrien-3-ol-20 one and 6 a-methyl-16a,17a-isopropylidenedioxy-A 19 nor pregnatrien-3-o l-20-one wereconverted into the correspondin 3-methyl ethers.

Example XX In accordance with the method described in the precedingexample, 1 g. of the 17,20;20,2l-bismethylenedioxy A-l9-nor-pregnatrien-3-ol was treated with dimethyl sulfate in acetoneandin the presence of potassium hydroxide, to produce3-methoXy-17,20;20,2l-bismethylenedioxy A -19-nor-pregnatriene, whichupon hydrolysis with 60% formic acid, in accordance with the methoddescribed in Example XIV, gave 3-methoxy-A -19-nor-pregnatriene-l7a,2l-diol-ZO-one.

Example XXI A mixture of 500 mg. of 6a-ethinyl-estrone, 4 cc. ofpyridine and 2 cc. of acetic anhydride was kept at room temperature for4 hours, poured into ice water and the formed precipitate collected byfiltration, washed with water and dried. Crystallization fromacetone-hexane gave the acetate of '6a-ethinyl-estrone.

Example XXII A solution of 2 g. of 6a,17a-dimethyl estradiol in 8 cc. ofpyridine was treated with 4 cc. of benzoyl chloride and then heated onthe steam bath for 1 hour. The mixture was then poured into ice waterand the formed precipitate collected, washed with water and dried.Recrystallization from methylene chloride-hexane afforded the 3-benzoateof 6a,l7a-dimethyl-estradiol.

Example XXIII In accordance with the method described in Example ,XXIthe compounds mentioned below under I were treated with the indicatedacid anhydride, to produce the respective mono or di-esters II:

was treated dropwise with 4 cc. of dimethyl sulfate.

Anhydride 6a-methyI-17a-vinylestradiol 6a-pr0pargyl-lM-methyl-estradiol6a,17a-diethinyl-estradiol A -19-nor-pregnatrien-3-o1-20- Propionic3-propionate of 6a-methyl-17a-vinylestradiol.

3-caproate of fia-propargyl-Uamethyl-estradiol.

Acetic 3-a1cet1ate of6a,17a-diethi.ny1-estra- 1o Acetic Acetate of A-19-nor-pregnatrien-3-ol-20-one. Cyclopentyl- Cyclopentylpropionate of16apropionic. methyl-A -19-nor-pregnatrien-B-ol ZO-onc. Acet1c Acetateof (la-methyl-A -19-norpregnatrien-ii-ol-ZO-onc. Enanthic Enanthate ofGwethinyl-A -19- nor-pregnatrien-3-0l-20-one. Caproic Caproate of6a-methy1-16a-17uisopropylidene-dioxy-A 19- nor-pregnatrien-3-ol-20-one.Propionic. 3-propionate of A -19-n0rpregnatriene-Ii,l7a-diol-20-one.Caproic 17-acetatc 3-caproate of A 19-nor-pregnatriene-3,17a-di0l-20-0nc. 3,21-diacetate of A-19-norpregnatriene-3,17a,21-tri0l-20-0ne.

A Q -19-nor-pregnatricne-3,17a, Propiom'c. 3,21-dipropionate of A-19-n0r- 21-tr1ol-1l,20-dione. grcgnatriene-B,17a,21-triol-11,20-

10116. 3-methoxy-A fiq -ltl-nor-pregna- Acetic 21-acetate of3-1nethoxy-A -19- meme-17 a,21-d1o1-20-one.nor-pregnatriene-17a,21-diol20- one.

The Example XXIV reaction mixture was stirred for minutes further,poured into a dilute hydrochloric acid solution and the formedprecipitate collected by filtration. Crystallization fromchloroform-methanol gave the pure 3-metlioxy-6aethinyl-est-rone.

In a similar manner, 6a,l7a-dimethyl-estradiol,cmethyl-l7a-vinyl-estradiol, 6a-propargyl 17a methylestradiol, A-19-nor-pregnatrien-3-ol-2O one, 6a-

To a solution of 1 g. of Got-methyl-17a-vinyl-estradiol in 30 cc. ofanhydrous benzene there were added 200 mg. of p-toluenesulfonic acid and4 cc. of acetic anhydride, and the reaction mixture was kept at roomtemperature for 24 hours, poured into ice water and the resultingmixture stirred to elfect the hydrolysis of the excess anhydride. Thebenzene layer was separated and washed with 10% sodium carbonatesolution and water. Drying,

9 evaporation and crystallization of the residue from etherhexaneafforded the diacetate of 6a-methyl-l7a-vinylestradiol.

By the same method the compounds below mentioned under I were treatedwith the indicated anhydride, thus 11. The process of claim 1 whereinthe oxidizing agent is sodium dichromate.

12. The process of claim 1 wherein the oxidizing agent isN-bromoacetamide.

13. The process of claim 1 wherein the oxidizing agent 5 yieldmg theproducts under II: is N-bromo-succimrnide.

I I Anhydride II 6a,17a-diethinyl-estradiol Propionic- Diproponlate of6a,17a-diethiny1- estra i A -19-nor-pregnatriene-3,17a- Acetic Diacetateof A -ltJ-nor-prcgnadiol--one. triene-3,17a-diol-20-one.6,17a-dimethy1-estradio1 Caproic Diczzprgatle of 6,17a-dimethy1- as re10 3-propionate of 6a-methyl-17a Enanthic 3-propionate, 17-enanthate of6avinyl-estradiol. methyl-17a-vinyl-estradiol.3-methoxy-6a,17a-dimethyl- Cyclopentyl- Oyclopentylpropionate of3-methoxy estradiol. propionic. Get-17a-dimethyl-estradiol.3-methoxy-Gu-rnethyl-lIa-vinyl- Acetic Acetate of3-rnethoxy-6a-methyl-17aestradiol. I vinyl-estradiol.

Example XXV In accordance with the method described in Example I, 5 g.of 17,20;20,21-bismethylenedioxy-6-ethinyl- A -l9-nor-pregnadiene-3fi-olwere converted into l7,20;20,21- bismethylenedioxy 6a ethinyl 11l9-nor-pregnatrien-3-ol.

The preceding compound was then submitted to the reactions described inExample XX to give 3-methoxy- 6a ethinyl Ammo) 19 nor pregnatrienel7u,2ldio1-2O-one.

Esterification of this compound with acetic, caproic andcyclopentylpropionic anhydrides in pyridine solution afforded theZI-acetate, 21-caproate and 21-cyclopentylpropionate of3-methoxy-6a-ethinyl-A -l9-nor-pregnatriene-17a,21-diol-20-one.

We claim:

1. A process for the production of 3-hydroxy-ring A aromatic steroidsselected from the group consisting ofthe androstane, pregnane andsapogenin series which comprises reacting a 3-hydroxy-A -l9-nor steroidselected from the group consisting of the androstane, pregnane andsapogenin series with an oxidizing agent capable of oxidizing secondaryalcohols to ketones.

2. A process for the production of 3-hydroxy-ring A aromatic steroidsselected from the group consisting of the androstane, pregnane andsapogenin series which comprises reacting a 3-hydroxy-A -l9-nor steroidselected from the group consisting of the androstane, pregnane andsapogenin series with an aluminum alkoxide inthe presence of a hydrogenacceptor.

.3. The process of claim 2 wherein the reagent used is aluminumisopropoxide in toluene solution and in the presence of cyclohexanone.

4. The process of claim 2 wherein the aluminum alkoxide is aluminumt-butoxide.

5. The process of claim 2 wherein the aluminum alkoxide is aluminumphenoxide.

6. The process of claim 2 wherein the hydrogen acceptor is acetone.

7. The process of claim 2 wherein the hydrogen acceptor is benzoquinone.

8. The process of claim 1 wherein the oxidizing agent ischr-omium-trioxide in aqueous acetic acid.

9. The process of claim 1 wherein the oxidizing agent is thechromium-trioxide-pyridine complex.

10. The process of claim 1 wherein the oxidizing agent is an 8N solutionof chromium trioxide in acetone and in the presence of sulfuric acid.

14. A compound of the following formula:

R is selected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl radical of less than 12 carbon atoms; R is selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl and loweralkinyl; R is selected from the group consisting of hydrogen, loweralkyl and a lower acyl group; and X is selected from the groupconsisting of lower alkyl, lower alkenyl and lower alkinyl radicals of 2to 6 carbon atoms.

15. 6a-vinyl estradiol.

16. 6oc-ethinyl estradiol.

17. 6u-vinyl-estrone.

18. 6a-ethiny1-estrone.

19. A compound of the following formula:

t C=O wherein R is selected fromthe group consisting of hydrogen, alower alkyl group and an acyl group of less than 12 carbon atoms; R isselected from the group consisting of hydrogen, hydroxy and ahydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R isselected from the group consisting of hydrogen,

u-methyl, fi-methyl, a-hydroxy and a-acyloxy; R and R together representthe grouping of up to 6 carbon atoms.

20. A compound of the following formula:

OHzOR wherein R is selected from the, group consisting of hydrogen and ahydrocarbon carboxylic acyl radical of less than 12 carbon atoms; R isselected from the group consisting of hydrogen, a lower alkyl group andan acyl group of less than 12 carbon atoms; R is selected from the groupconsisting of hydrogen, tat-methyl, fi-methyl, u-hydroxy rand a-acyloxy;R together with the hydroxyl group at C-l7 represent the groupingwherein A is selected from the group consisting of hydrogen and a loweralkyl radical and B is selected from the group consisting of loweralkyl, aryl and aralkyl radicals; X is selected from the groupconsisting of lower alkyl, lower alkenyl and lower alkinyl radicals ofup to 6 carbon atoms; and Z is selected from the group consisting ofhydrogen, fi-hydroxy and keto.

No references cited.

LEWIS Gorrs, Primary Examiner.

ELBERT L. ROBERTS, Examiner.

20. A COMPOUND OF THE FOLLOWING FORMULA: